Cardiac adenoviral S100A1 gene delivery rescues failing myocardium
Patrick Most, … , Andrew Remppis, Walter J. Koch
Patrick Most, … , Andrew Remppis, Walter J. Koch
Published December 1, 2004
Citation Information: J Clin Invest. 2004;114(11):1550-1563. https://doi.org/10.1172/JCI21454.
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Article Cardiology

Cardiac adenoviral S100A1 gene delivery rescues failing myocardium

Abstract

Cardiac-restricted overexpression of the Ca2+-binding protein S100A1 has been shown to lead to increased myocardial contractile performance in vitro and in vivo. Since decreased cardiac expression of S100A1 is a characteristic of heart failure, we tested the hypothesis that S100A1 gene transfer could restore contractile function of failing myocardium. Adenoviral S100A1 gene delivery normalized S100A1 protein expression in a postinfarction rat heart failure model and reversed contractile dysfunction of failing myocardium in vivo and in vitro. S100A1 gene transfer to failing cardiomyocytes restored diminished intracellular Ca2+ transients and sarcoplasmic reticulum (SR) Ca2+ load mechanistically due to increased SR Ca2+ uptake and reduced SR Ca2+ leak. Moreover, S100A1 gene transfer decreased elevated intracellular Na+ concentrations to levels detected in nonfailing cardiomyocytes, reversed reactivated fetal gene expression, and restored energy supply in failing cardiomyocytes. Intracoronary adenovirus-mediated S100A1 gene delivery in vivo to the postinfarcted failing rat heart normalized myocardial contractile function and Ca2+ handling, which provided support in a physiological context for results found in myocytes. Thus, the present study demonstrates that restoration of S100A1 protein levels in failing myocardium by gene transfer may be a novel therapeutic strategy for the treatment of heart failure.

Authors

Patrick Most, Sven T. Pleger, Mirko Völkers, Beatrix Heidt, Melanie Boerries, Dieter Weichenhan, Eva Löffler, Paul M.L. Janssen, Andrea D. Eckhart, Jeffrey Martini, Matthew L. Williams, Hugo A. Katus, Andrew Remppis, Walter J. Koch

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Figure 6

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S100A1 interacts with SERCA2 and increases activity of the SR Ca2+ pump ...
S100A1 interacts with SERCA2 and increases activity of the SR Ca2+ pump in COS cells. (A) Representative Western blots given for adenovirally expressed S100A1 and SERCA2 in COS cells. β-Actin staining served as loading control. (B) Left: Enhanced Ca2+-dependent ATPase activity in SERCA2-expressing COS cells by coexpressed S100A1 protein. Expression of S100A1 alone did not alter Ca2+-dependent ATPase activity in COS cells. Note that addition of anti-S100A1 antibody abrogated the S100A1-mediated increase in Ca2+-dependent ATPase activity. Right: Increased Ca2+-dependent ATPase activity in SERCA2-expressing COS cells following application of human recombinant S100A1 protein (rh-S100A1, 1 μM). Application of anti-S100A1 antibody (10μl) abrogated the S100A1-mediated enhancement of Ca2+-dependent ATPase activity. Application of the SERCA2 inhibitor thapsigargin (10_6 M) abolished Ca2+-dependent ATPase activity in AdSERCA2-infected COS cells. Experiments were carried out at pCa 6.2 (n = 3). *P < 0.01 vs. AdSERCA2; **P < 0.01 vs. AdS100A1/AdSERCA2. Data are presented as mean ± SEM. (C) Ca2+-dependent coimmunoprecipitation of SERCA2 (red) and S100A1 (green). Samples were immunoprecipated with anti-S100A1 antibody and costained for SERCA2. Control experiments were carried out with an anti-S100A1 antibody preincubated with a blocking peptide.